Daphne Atlas, Ph.D. M.Sc, Professor of Neurochemistry, Dept. of Biological Chemistry, Institute of Life Sciences, The Hebrew University of Jerusalem
Autism spectrum disorder (ASD) is a heterogeneous disorder initiated early in development and characterized by abnormal social communication. A special case of autism is known as Timothy Syndrome (TS), which is caused by a point mutation in the calcium channel Ca v 1.2. TS is a multisystem disorder characterized also by cardiac arrhythmias.
We are studying two TS mutations, G406R and G402S, that occur in Ca v 1.2. These mutations cause an abnormal calcium overload leading to a cardiac arrhythmia. Surprisingly, only the G406R mutation is associated with ASD in 4 of 5 patients carrying the mutation in our study, while the G402S mutation fails to express the autistic phenotype.
Our study sought to answer the question: How does the G406R single point mutation of the Ca v 1.2 channel affect cellular processes that could lead to a multifactorial disease such as autism? It is known that Ca v 1.2 and other calcium channels induce gene expression. Mutant calcium channels can lead to defects in long-term processes, such as neurodevelopmental disorders and psychiatric disorders including schizophrenia, bipolar disorder and autism.
The researchers, led by Professor Daphne Atlas at the Hebrew University of Jerusalem’s Alexander Silberman Institute of Life Sciences, found that both the Ca v 1.2 TS mutants G406R and G402S activate gene expression programs (transcriptional activity) via the Ras/ERK/CREB pathway, similar to the non mutated Ca v 1.2 channel. “We were surprised to discover that the autistic mutant G406R exhibits a constitutive (spontaneous) transcriptional activation and the G402S mutation does not.” This difference might clarify why G406R mutation confers autism whereas G402S does not“ shared Atlas.
The research findings of spontaneous activity of the G406R channel correlates with a constitutive activation of gene expression. This uncontrolled spontaneous gene activation, implies a possible mechanism. Indeed, the G406R and other calcium channel autistic mutants, as opposed to G402S, display a negative shift in voltage activation, which facilitates spontaneous activity. This shift in channel activation is the mechanism that might serve to predict and diagnose ASD affected individuals. The spontaneous activity of the channel and subsequently spontaneous gene activation can be compared to a dripping faucet.
These findings imply that the TS G406R mutant exhibits deregulated channel activity at rest – without stimulation – and is likely to exhibit spontaneous and uncontrolled gene expression. Other channel mutants associated with long-term disabilities display similar shifts in channel activation kinetics.
“Further studies are required to establish whether the uncontrolled activity of the channel at rest, which is associated with uncontrolled activation of gene programs in the TS G406R mutant, is the underlying mechanism by which other mutated channels confer a high risk for neurodevelopmental disorders in humans,” explained Atlas.
The study was published in Progress in Neurobiology. It is part of a PhD thesis by Evrim Servili and was done in collaboration with fellow HU colleagues, Drs. Michael Trus, Eilon Sherman and Julia Sajman.
Elevated basal transcription can underlie timothy channel association with autism related disorders. Servili E, Trus M, Sajman J, Sherman E, Atlas D. Prog Neurobiol. 2020 Aug; 191:101820. doi: 10.1016/j.pneurobio.2020.101820. Epub 2020 May 11. PMID: 32437834
This research was supported by the H. L Lauterbach Family Fund.
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